OVERPRODUCTION OR APOB IS FREQUENT IN FCHL, A GENETICALLY HETEROGENEOUS DISORDER. IN MOST FCHL CASES, HMGCOA REDUCTASE INHIBITORS DECREASE APOB LEVELS BE DECREASING APOB PRODUCTION. WE REPORT AN UNUSUAL KINDRED WITH LOW VLDL- AND LDL-APOB FCR AS THE MAIN KINETIC DEFECTS. FIVE MEMBERS OF THE KINDRED, 3 WITH MIXED HYPERLIPIDEMIA, 1 HYPERCHOLESTEROLEMIA AND 1 HYPERTRIGLYCERIDEMIA, PARTICIPATED IN A DOUBLE BLIND, RANDOMIZED, PLACEBO-CONTROLLED CROSSOVER STUDY. SIX WEEK TREATMENT PERIODS WERE SEPARATED BY 2 WEEK WASHOUTS. PRAVASTATIN (20MG/DAY) LOWERED PLASMA CHOLESTEROL (212117 VS 268126 MG/DL, P<0.05), LDL CHOLESTEROL (14218.7 VS 185131 MG/DL, P<0.05), AND APOB (124112 VS 169115.5 MG/DL, P<0.05), BUT DID NOT CHANGE HDL CHOLESTEROL OR LP(A). METABOLIC PARAMETERS OF APOB WERE DETERMINED WITH THE ENDOGENOUS LABEL C13-LEUCINE AND A MULTICOMPARTMENTAL MODEL. DURING PLACEBO TREATMENT VLDL APOB FCRS WERE 3.611.1 VS 9.212.9 POOLS/DAY FOR 9 NORMOLIPIDEMIC CONTROLS. LDL APOB FCRS WERE 0.1910.05 VS 0.4110.13. VLDL APOB PRODUCTION WAS NORMAL. MOST LDL WERE IN THE DENSITY RANGE 1.036 < D < 1.063 G/ML AND HAD FCRS OF 0.2210.08. FCRS OF LIGHT LDL WERE 0.8210.21. PRAVASTATIN INCREASED LDL APOB FCRS IN ALL CASES FROM 0.1910.05 TO 0.3410.04. BOTH LDL SUBCLASSES WERE SIMILARLY AFFECTED. WE CONCLUDE THAT FCHL IS KINETICALLY HETEROGENEOUS AND THAT IN THIS KINDRED PRAVASTATIN LOWERED LDL LEVELS BY INCREASING THE LDL FCR.